脓毒症指由感染引起的全身炎症反应综合征，进一步发展可导致脓毒性休克、多器官功能衰竭，是临床危重病患者最主要的死亡原因。尽管抗菌素在临床上广泛使用，但随着细菌抗药性的产生，临床治疗脓毒症的效果至今未见明显改善，迫切需要发展新的治疗脓毒症的思维和方法。我们前期的研究发现丝裂原活化蛋白激酶磷酸酶 1（MKP-1）可以通过负性调节NF-kappaB的活化，控制炎症介质的产生，降低脓毒性休克动物的死亡率；抗炎药物硌利普兰（Rolipram）可通过增强MKP-1的表达抑制NF-kappaB的活化，减轻炎症反应和肺组织损伤。本项目拟在上述发现的基础上，分别从分子、细胞和整体水平，利用基因敲除、RNA干扰、基因转染、液相芯片等技术，进一步探讨MKP-1在脓毒症中的作用机理，深入研究新型抗炎药物硌利普兰治疗脓毒症的效果及其机理，为脓毒症和脓毒休克的临床治疗寻求新的治疗药物和策略。

Sepsis is a systemic inflammatory response syndrome caused by bacterial infections,when further developing it can lead to septic shock, multiple organ failure(MOF),which are the most important cause of death of the clinical critically ill patients. Althrough the antibiotics have been widely used in the clinical,but with the emergence of antibiotic-resistant bacterial strains, its clinical effect for sepsis has not been significantly improved. Consepuently,development of novel therapeutic strategies is urgently needed for the treatment of septic shock and multiple organ failure. Our previous studies found that the mitogen-activated protein kinase phosphatase-1 (MKP-1) can regulate the production of inflammatory mediators and reduce the mortality of septic shock animals through the negative regulator of NF-kappaB activation. Our results also indicated that Rolipram, which has already been used for chronic obstructive pulmonary disease (COPD), inhibits the activation of NF-kappaB, reduces inflammation response and lung tissue damage by enhancing the expression of MKP-1. Therefore, Rolipram may act as an anti-sepsis agent for septic shock. Based on these interesting and important findings, the primary objectives of this study are targeted toward completing the preclinical development of Rolipram as a novel therapeutic agent in reducing mortality of septic shock and multiple organ failure, as well as determining the mechanism responsible for its beneficial effect both in vitro and in vivo by using gene knockout, RNA interference, gene transfection, liquid chips and other technology. These proposed studies should provide useful mechanisms and preclinical information that will allow us to initiate clinical studies for Rolipram in victims with septic shock and multiple organ failure.